Inhibition of SAM binding to CBS |
Partial inhibition of CBS catalytic activity. Destabilization of the CBS tetramer |
MAT inhibitors, competitors of SAM binding to CBS (SAM analogs) |
Inhibition of other SAM-dependent enzymes and processes |
Stimulation of CO or NO binding to CBS |
Partial inhibition of CBS catalytic activity |
NO or CO donors |
Activation other NO- or CO-dependent enzymes and processes (e.g., vasodilatation, hypotension) |
Inhibition of CBS phosphorylation |
Partial inhibition of CBS catalytic activity |
Kinase inhibitors |
Inhibition of other enzymes phosphorylated by the same kinase; modulation of multiple downstream processes |
Inhibition of CBS S-glutathionylation |
Partial inhibition of CBS catalytic activity |
Glutathione S-transferase inhibitors |
Inhibition of other enzymes glutathionylated by the same S-transferase |
Stimulation of SUMOylation |
Proteolytic degradation of CBS; reduced total cellular CBS activity |
Possible approach may be the modulation of upstream processes, e.g., E1 activating enzyme (the heterodimer SAE1/2) or E2 conjugase (Ubc9). No known pharmacological agents |
Broad dysregulation of protein processing and protein degradation |
Stimulation of ubiquitination |
Proteasomal degradation of CBS; reduced total cellular CBS activity |
Pharmacological activation of E1 activating, E2 conjugating and E3 ligating enzymes (only theoretical; no known inhibitors). Or: pharmacological inhibition of deubiquitinases (this approach has been proposed to degrade undruggable targets for cancer therapy) |
Broad dysregulation of protein processing and protein degradation |
Inhibition of CBS proteolytic cleavage |
Inhibition of the proteolytic conversion of CBS into the highly active 45-kDa form; inhibition of cellular CBS activity |
Proteolysis inhibitors (not suitable as a practical approach; selective intracellular delivery of protease inhibitors is not feasible) |
Broad dysregulation of protein processing and protein degradation |
Activation of Lon protease |
Proteolytic degradation of CBS into inactive forms |
Lon activators (e.g., Heat Shock Protein Q) exist but only as experimental tools |
Broad dysregulation of mitochondrial protein homoeostasis |
Inhibiting substrate availability by blocking cystine transport into the cell |
Lower CBS activity |
Cystine/glutamate antiporter system blockers |
Broad dysregulation of sulfur-containing amino acid homeostasis |